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Abstract Systemic sclerosis (SSc) is an idiopathic systemic connective tissue disorder characterized by fibrosis of the skin and internal organs, with growing interest in the imbalance between Th17 cells and regulatory T cells (Tregs) in the disease’s pathogenesis. Heligmosomoides polygyrus (Hp), a natural intestinal parasite of mice, is known to induce Tregs in the host. We aimed to investigate the effects of Hp-induced Tregs on bleomycin-induced dermal fibrosis and clarify the role of the Th17/Treg balance in SSc fibrosis. Infection with Hp suppressed the development of bleomycin-induced dermal fibrosis and the infiltration of CD3+ T cells and CD68+ macrophages. Flow cytometric analysis revealed that Hp infection increased Tregs and inhibited the induction of bleomycin-induced Th17 cells. Treg depletion nullified these effects, suggesting that Hp-induced Tregs may prevent bleomycin-induced dermal fibrosis and inflammation. Analysis of the intestinal microbiota showed that bacteria positively correlated with Tregs exhibited a negative correlation with Th17 cells and dermal fibrosis in mice. SSc patients with severe fibrosis displayed a distinct microbiota profile. These results suggest that alterations in the intestinal microbiota may contribute to the Th17/Treg imbalance in SSc and its progression. Enhancing Tregs to regulate the Th17/Treg imbalance may present a promising strategy for suppressing fibrosis in SSc.

Alopecia areata (AA) is a chronic immune-mediated skin disorder characterized by non-scarring hair loss. Although clinical trials have shown the effectiveness and safety of baricitinib, there are limited reports that have shown real-world evidence of baricitinib in patients with AA. Herein, we present the real-world data of 17 Japanese adult patients with AA treated with baricitinib at Gunma University Hospital, Japan, for 60 weeks. All patients received 4 mg of baricitinib daily without interruption. The SALT20 achievement was 29.4% (5/17) at week 24, 52.9% (9/17) at week 36, 58.9% (11/17) at week 48, and 64.7% (11/17) at week 60. Patients were categorized as early responders (n = 1), gradual responders (n = 8), late responders (n = 3), and non-responders (n = 5). Exacerbations of alopecia occurred in only one patient. Eleven patients experienced improvement in scalp hair loss at week 12, leading to a significant reduction in the AA-IGA score. At week 24, improvements in eyebrows and eyelashes were noted in 12 and 11 patients, respectively, with significant reductions in their ClinRO scores. The duration of the current episode of AA exceeding 4 years significantly reduced the SALT20 achievement rate (p < 0.027). Common adverse effects included acne (n = 4, 23.5%) and mildly decreased renal function (n = 2, 11.7%). In conclusion, our findings indicate that baricitinib has significant potential for improving intractable severe AA.

Over the past decade, significant advancements in stem cell research led by mesenchymal stem cells (MSCs) have facilitated their practical application in clinical settings, including inflammatory skin diseases. Urine-derived stem cells (USCs) are obtained from healthy human urine in a noninvasive approach with properties similar to mesenchymal stem cells (MSCs). However, the therapeutic potential of USCs for inflammatory skin diseases has not yet been fully explored. Herein, we report the therapeutic effects of USCs-derived culture supernatants on mice with psoriasis-like dermatitis using our originally established human USCs model. We examined the isolation of USCs from human urine using a simple centrifugation process. Cell markers related to MSCs-like cell were positive for CD29, CD44, CD73, CD90, and negative for HLA-DR, CD34, and CD45 by FACS analysis. Differentiation assays revealed that the cells possessed the capability to differentiate into adipocytes, chondrocytes, and osteocytes. USCs-conditioned medium (CM) treatment significantly suppressed the severity of dermatitis in imiquimod (IMQ)-treated psoriasis mice model. Histopathological examination revealed that USCs-CM treatment attenuated epidermal thickness and the numbers of infiltrating inflammatory cells, including neutrophils, T-cells, and macrophages in dermatitis-affected areas in IMQ-treated psoriasis mice. Furthermore, USCs-CM treatment decreased mRNA levels of IL-17A, IL-17F, and IL-23p19 was reduced in dermatitis area. In summary, our findings revealed new potential strategies for utilizing USCs and USCs-CM as therapeutic agents for inflammatory skin diseases, including psoriasis.

Purpose: Recent radiation therapy (RT), such as intensity modulated radiation therapy and particle RT, has improved the concentration of the radiation field targeting tumors. However, severe adverse effects still occur, possibly due to genetic factors in patients. We aimed to investigate the mechanism of exacerbated inflammation during RT. Methods and Materials: Dermal fibroblasts derived from a patient with severe inflammatory adverse effects during RT were compared with 2 normal human dermal fibroblasts. Micronuclei formation, G2/M-checkpoint arrest, DNA damage signaling and repair, and inflammatory gene expression were comprehensively examined. Results: We found greater micronuclei formation in radiation-sensitive fibroblasts (RS-Fs) after ionizing radiation (IR). RS-Fs exhibited premature G2/M-checkpoint release after IR, which triggers micronuclei formation because RS-Fs undergo mitosis with unrepaired DNA double-strand breaks (DSBs). Additionally, we found that DSB end-resection and activation of the ATR-Chk1 pathway were impaired in RS-Fs after IR. Consistent with the increase in the formation of micronuclei, which can deliver cytosolic nucleic acids resulting in an innate immune response, the expression of genes associated with inflammatory responses was highly upregulated in RS-Fs after IR. Conclusions: Although this is a single case of RT-dependent adverse effect, our findings suggest that impaired G2/M-checkpoint arrest due to the lack of DSB end-resection and activation of the ATR-Chk1 pathway causes exacerbated inflammation during RT; therefore, genes involved in G2/M-checkpoint arrest may be a predictive marker for unexpected inflammatory responses in RT.

Abstract Objective Dupilumab has been deemed highly effective for atopic dermatitis (AD). However, there have been no reports performing a combination analysis with hematological data and improvement rates pertaining to the continued use of dupilumab for up to 2 years in real world. In this study, we evaluated the effectiveness and safety of using dupilumab for up to 2 years in 9 patients with AD at our hospital. Methods Thirty‐six patients with moderate‐to‐severe AD treated by dupilumab, and 9 of them treated for 2 years. Changes in the severity scoring, pruritus numerical rating scale (NRS), patient‐oriented eczema measure (POEM), serum levels of immunoglobulin E (IgE), thymus and activation‐regulated chemokine (TARC), eosinophils, and lactate dehydrogenase (LDH) at Week 0, 2, 4, 16, 48, 72, and 96 of those patients were investigated, and we studied features of the patients who had any adverse events (AEs). Results Investigator’s global assessment (IGA), eczema area and severity index (EASI), body surface area (BSA), NRS, POEM, and serum levels of LDH were significantly decreased from Week 4 onwards to Week 96 compared with baseline condition. Serum levels of TARC and LDH were significantly decreased from Week 4 onwards to Week 96. Regarding 9 patients who were treated with dupilumab for up to 2 years, serum levels of TARC and eosinophils decreased without statistical significance. The serum levels of IgE significantly decreased at Week 72, 96 compared with the baseline. Regarding as AEs, ocular symptoms were the most frequently observed (15/36, 41.2%), and there were no cases of discontinuation due to AEs. Conclusions Treatment with dupilumab was well tolerated and showed improvements in AD for at least 2 years.

Abstract Rosai–Dorfman disease (RDD) is a rare non‐Langerhans cell histiocytosis that was first described as sinus histiocytosis with massive lymphadenopathy by Rosai and Dorfman in 1969. While classical/nodal RDD is typical, extranodal involvement is seen in up to 43% of all cases, with 23% showing only extranodal lesions. Here, we present a case of disseminated extranodal RDD, where the initial symptoms were cutaneous manifestations.

We present four Japanese patients with prurigo‐type AD who received upadacitinib. Rapid improvement of skin lesions and itchiness was seen in all patients. Janus kinase inhibitor is effective for prurigo‐type AD by strongly suppressing itching.

We present a rare case of a patient with AD who developed tinea corporis during upadacitinib treatment in a real‐world clinical setting. We hypothesized that the suppressive effect of Th17 immunity by upadacitinib possibly has contributed to the development of tinea corporis.

The Ehlers–Danlos Syndromes (EDS), a group of hereditary connective tissue disorders, were classified into 13 subtypes in the 2017 International Classification. Recently, a new subtype of EDS called classical-like EDS type 2 (clEDS2), which is caused by biallelic variants in the adipocyte enhancer binding protein 1 (AEBP1) gene, was identified. We describe the 11th patient (9th family) with clEDS2, who was complicated by a critical vascular event (superior mesenteric artery aneurysm and rupture). A next-generation sequencing panel-based analysis revealed compound heterozygous variants in AEBP1: NM_001129.5:c.[2296G>T]; [2383dup], p.[(Glu766*)]; [(Glu795Glyfs*3)]. Light microscopic analyses showed increased interfibrillar spaces in the reticular dermis, a disorganized arrangement of collagen fibers, and decreased collagen content. An electron microscopic analysis showed the presence of collagen fibrils with irregular contours (flower-like appearance) and small collagen fibrils. A biochemical analysis showed reduced secretion of type I and type III procollagen. Clinical and molecular features of the current patient and all previously reported patients were reviewed comprehensively. Manifestations noted in most cases (>80%) included skin features (hyperextensibility, atrophic scars, easy bruising, excessive skin/skin folding, delayed wound healing, translucency, piezogenic papules), skeletal features (generalized joint hypermobility, dislocations/subluxations, pes planus), dental abnormalities, and neuromuscular abnormalities. Critical complications, each occurring in a single case, included superior mesenteric artery multiple aneurysm and rupture, aortic root dilation requiring surgery, and bowel rupture. Most AEBP1 variants were predicted or experimentally confirmed to lead to nonsense-mediated mRNA decay, whereas one variant resulted in a protein that was retained intracellularly and not secreted. Clinical, molecular, pathological, and biochemical features of the current patient, as well as a review of all previously reported patients, suggest the importance of the aortic carboxypeptidase-like protein encoded by AEBP1 in collagen fibrillogenesis.

Abstract Objectives It has been known that the use of moisturizers is useful in preventing the onset and maintaining remission of atopic dermatitis (AD). We recently focused on the moisturizing effect of natural mineral dissolved water and have conducted various studies. In this study, we investigated whether the bath treatment using natural mineral dissolved water can improve dry skin in AD patient in prospective nonblind, nonrandomized controlled study. Methods Thirteen adults with almost clear to moderate AD took bath therapy using tap water for 13 days, followed by bath therapy using natural mineral dissolved water for 13 days. Changes in the severity scoring, patient‐oriented eczema measure, pruritus numerical rating scale, transepidermal water loss (TEWL) and hydration were evaluated at day1, 14 and 28. Results Tap water using bath treatment did not change the severity scoring and itch associated score, and it partially decrease TEWL when compared with baseline condition. Bath treatment using natural mineral dissolved water slightly decrease eczema area and severity index (EASI) score and significantly decrease TEWL with respect to baseline condition. Moreover, in relatively severe AD analysis, bath treatment with mineral dissolved water significantly decreased EASI and TEWL. Conclusions Based on these results, bathing with natural mineral dissolved water may be effective in improving the dry skin of atopic dermatitis. Further studies are needed to evaluate its effects more clearly.

Over the past decade, significant advancements in stem cell research led by mesenchymal stem cells (MSCs) have facilitated their practical application in clinical settings, including inflammatory skin diseases. Urine-derived stem cells (USCs) are obtained from healthy human urine in a noninvasive approach with properties similar to mesenchymal stem cells (MSCs). However, the therapeutic potential of USCs for inflammatory skin diseases has not yet been fully explored. Herein, we report the therapeutic effects of USCs-derived culture supernatants on mice with psoriasis-like dermatitis using our originally established human USCs model. We examined the isolation of USCs from human urine using a simple centrifugation process. Cell markers related to MSCs-like cell were positive for CD29, CD44, CD73, CD90, and negative for HLA-DR, CD34, and CD45 by FACS analysis. Differentiation assays revealed that the cells possessed the capability to differentiate into adipocytes, chondrocytes, and osteocytes. USCs-conditioned medium (CM) treatment significantly suppressed the severity of dermatitis in imiquimod (IMQ)-treated psoriasis mice model. Histopathological examination revealed that USCs-CM treatment attenuated epidermal thickness and the numbers of infiltrating inflammatory cells, including neutrophils, T-cells, and macrophages in dermatitis-affected areas in IMQ-treated psoriasis mice. Furthermore, USCs-CM treatment decreased mRNA levels of IL-17A, IL-17F, and IL-23p19 was reduced in dermatitis area. In summary, our findings revealed new potential strategies for utilizing USCs and USCs-CM as therapeutic agents for inflammatory skin diseases, including psoriasis. [ABSTRACT FROM AUTHOR]

Abstract is missing (Short communication)

Objectives: Non-surgical treatment is an acceptable approach for managing appendiceal abscess in adults. However, it is only applicable for selected patients, and conversion to surgery is mandatory for failed conservative treatment. This study aimed to determine the predictive factors for unsuccessful outcomes. Methods: Of 594 patients with acute appendicitis, 34 (5.7%) diagnosed with appendiceal abscess were initially treated conservatively. Patients were divided into two groups: the conservative group, which was successfully treated with antibiotics and percutaneous abscess drainage, and the conversion group, which comprised patients who had surgical conversion despite conservative treatment. Risk factors for the conversion group were investigated by comparing clinical and radiological parameters between the two groups. Results: Eight (23.4%) patients were converted to surgical management at an average of 5.5 days of non-surgical treatment. An abscess size greater than 40 mm and a lower rate of improvement in the white blood cell (WBC) count were significant factors for predicting conversion in multivariate analysis. The conversion group had a long operative time and high morbidity and operative conversion rates (change of proposed initial operation). Early conversion to operation group, i.e., less than 5 days of treatment, contributed to a significantly shorter hospital stay, lower hospital cost, and relatively shorter operative time (p = 0.02, p = 0.04, and p = 0.11, respectively). Conclusions: Contributing factors in predicting unsuccessful outcomes for non-surgical treatment include an abscess size greater than 40 mm and a low rate of improvement in WBC count on the first day of antibiotic treatment.

Background/objective: Laparoscopic gastrectomy (LG) is increasingly used to treat gastric cancer. Simultaneously, internal hernia (IH) has been reported after LG with Roux-en-Y reconstruction (RY). The aim of this study was to investigate IH after LG with RY for gastric cancer. Methods: This study included 15 patients with IH from a database of 355 consecutive patients who underwent LG with RY for gastric cancers. We retrospectively analyzed IH incidence and clinical characteristics by operative procedures. Results: The total incidence of IH was 4.2%. The incidence of IH at Petersen's defect tended to decrease with modifications to the reconstruction methods, but not significantly so. The incidence of IH at jejunojejunostomy mesenteric defect significantly decreased with closure of this defect (p = 0.01). The incidence of IH at transverse mesocolic defect was 1.3% in patients who underwent retrocolic RY; emergent small-bowel resection was only required in two cases of herniation through this defect after laparoscopic total gastrectomy. Conclusion: Retrocolic RY with appropriate closure of defects can reduce IH incidence at Petersen's defect and at jejunojejunostomy mesenteric defect. Although the IH incidence at the transverse mesocolic defect is not particularly high, the possibility of herniation through this defect should be kept in mind.